Results from a post-hoc analysis from the Phase 3 TROPiCS-02 study evaluating sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences) versus comparator chemotherapy (physicians’ choice of chemotherapy, TPC) in patients with HR+/HER2- metastatic breast cancer who progressed on endocrine-based therapies and at least two chemotherapies, demonstrated that recently approved agent benefits patients.[1][2][3][4]

In the analysis, sacituzumab govitecan improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with TPC across Trophoblast cell-surface antigen-2 (Trop-2) expression levels.

The details of the anaysis were presented in a late-breaking abstract at the 2022 San Antonio Breast Cancer Symposium at the Henry B. Gonzalez Convention Center, San Antonio, Tx. (SABCS, Abstract #GS1-11).

Sacituzumab govitecan is a first-in-class Trop-2 directed antibody-drug conjugate (ADC). Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Sacituzumab govitecan is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

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Improved PFS and OS
“Sacituzumab govitecan improved both progression-free survival and overall survival in pre-treated HR+/HER2- metastatic breast cancer in the Phase 3 TROPiCS-02 study compared to standard chemotherapy options,” noted Hope S. Rugo, MD, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center.

“This post-hoc analysis demonstrates that the level of Trop-2 expression on an individual’s tumor did not impact sacituzumab govitecan efficacy,” Rugo added.

Hope S. Rugo, MD, FASCO, is professor of medicine in the Division of Hematology and Oncology at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, where she is also the director of Breast Oncology and Clinical Trials Education.

“These data can give us confidence in the potential benefit of sacituzumab govitecan for patients with endocrine-resistant metastatic breast cancer who have progressed on available chemotherapies, across Trop-2 expression levels.”

Trophoblast cell-surface antigen-2
Trop-2, a protein found on the surface of cancer cells, is involved in several cellular processes regulating cancer growth and invasion. It is highly expressed in most human solid tumors, including more than 90% of breast cancers.

In the TROPiCS-02 study, Trop-2 expression was measured by immunohistochemistry and expressed as a histochemical score (H-score; range, 0-300).

Efficacy outcomes were assessed across H-score groups, including those with very low Trop-2 expression. Across each H-score subgroup, Trodelvy demonstrated improved PFS, OS and ORR compared to TPC, which is consistent with the PFS, OS and ORR in the TROPiCS-02 intention-to-treat population.

“The prognosis for patients with pre-treated HR+/HER2- metastatic breast cancer who have developed resistance to endocrine-based therapies has been poor, and these TROPiCS-02 study results demonstrate clinical efficacy with sacituzumab govitecan, across Trop-2 expression levels,” said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology.

“Our ambition is to continue our impact beyond our current approval in second-line metastatic Triple Negative Breast Cancer (TNBC), and we look forward to advancing discussions with the U.S. FDA and global health authorities to help bring sacituzumab govitecan to more people living with metastatic breast cancer.”

The safety profile for sacituzumab govitecan in TROPiCS-02 was consistent with prior studies, with no new safety signals identified in this population.

Additional data
Detailed statistically significant and clinically meaningful PFS and OS results from the Phase 3 TROPiCS-02 study were presented at the 2022 annual meeting of the American Society of Clinical Oncology (ASCO; Abstract #LBA1001).

During the ASCO meeting, presented data confirmed that the study met its primary endpoint of progression-free survival (PFS) with a statistically significant and clinically meaningful 34% reduction in the risk of disease progression or death (median PFS 5.5 vs. 4 months; HR: 0.66; 95% CI: 0.53-0.83; P<0.0003). The first interim analysis of the key secondary endpoint of overall survival (OS) further demonstrated a trend in improvement.

Results presented during the 2022 ASCO meeting also demonstrated that at the one-year mark, three times as many patients were progression-free when treated with Trodelvy compared to those who received TPC (21% versus 7%). Improvements in PFS with Trodelvy were also consistent across key patient subgroups, including patients who had previously received three or more chemotherapy regimens for metastatic disease (HR: 0.70; CI: 0.52-0.95), patients with visceral metastasis (HR: 0.66; CI: 0.53-0.83), and the elderly (≥65 years of age; HR: 0.59; CI: 0.38-0.93).

“For patients with HR+/HER2- metastatic breast cancer, resistance to endocrine therapy is inevitable in almost all cases. The standard of care is then limited to sequential single agent chemotherapy, with declining response rates, disease control and quality of life,” explained Rugo.

“In TROPiCS-02, we enrolled heavily pre-treated patients with metastatic breast cancer who had disease progression following multiple lines of chemotherapy. To observe a clinically meaningful reduction in the risk of disease progression or death in these patients with limited treatment options is remarkable. Sacituzumab govitecan will be an important potential future treatment option for these patients,” she added.

A prespecified health related Quality of Life (hrQoL) analysis, one of the secondary endpoints using the EORTC QLQ-C30 instrument, also favored sacituzumab govitecan over TPC demonstrating meaningful benefit. In the evaluable population, improvements in global health status and fatigue with Trodelvy (n=234) compared with those who received TPC (n=207) were also observed.

Regulatory approval
Based on these data, the U.S. Food and Drug Administration (FDA) accepted for priority review the supplemental Biologics License Application (sBLA) for sacituzumab govitecan in adult patients with unresectable locally advanced or metastatic HR+/HER2- (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. The Prescription Drug User Fee Act (PDUFA) target action date is currently set for February 2023.

Summary of post-hoc analysis results by Trop-2 expression

Trop-2
expression,
H-score

n (SG/TPC)

Median PFS
(SG vs
TPC),
months

PFS Hazard
Ratio
(95%CI)

Median OS
(SG vs
TPC),
months

OS Hazard
Ratio
(95%CI)

<100

96/96

5.3 vs. 4.0

0.77
(0.54-1.09)

14.6 vs. 11.3

0.75
(0.54-1.04)

≥100

142/128

6.4 vs. 4.1

0.60
(0.44-0.81)

14.4 vs. 11.2

0.83
(0.62-1.11)

≤10

34/45

5.5 vs. 4.3

0.89
(0.51-1.57)

17.6 vs. 12.3

0.61
(0.34-1.08)

>10-<100

62/51

5.0 vs. 3.5

0.67
(0.42-1.07)

13.7 vs. 11.0

0.81
(0.54-1.23)

>10

204/179

5.6 vs. 4.0

0.62
(0.48-0.80)

14.1 vs. 11.1

0.82
(0.65-1.0)

H-score, histochemical score; OS, overall survival; PFS, progression-free survival; SG, sacituzumab govitecan; TPC, treatment of physician’s choice.

Clinical trials
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/HER2- Metastatic Breast Cancer (TROPiCS-02) – NCT03901339

Highlights of Prescribing Information
Sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences)[Prescribing Information]

Reference
[1] Rugo HS, Bardia A, Tolaney SM, Arteaga C, Cortes J, Sohn J, Marmé F, Hong Q, Delaney RJ, Hafeez A, André F, Schmid P. TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. Future Oncol. 2020 Apr;16(12):705-715. doi: 10.2217/fon-2020-0163. Epub 2020 Mar 30. PMID: 32223649.
[2] Kalinsky K, Diamond JR, Vahdat LT, Tolaney SM, Juric D, O’Shaughnessy J, Moroose RL, Mayer IA, Abramson VG, Goldenberg DM, Sharkey RM, Maliakal P, Hong Q, Goswami T, Wegener WA, Bardia A. Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial. Ann Oncol. 2020 Dec;31(12):1709-1718. doi: 10.1016/j.annonc.2020.09.004. Epub 2020 Sep 15. PMID: 32946924.
[3] SG Improves OS in HR+/HER2- Breast Cancer. Cancer Discov. 2022 Dec 2;12(12):2714-2715. doi: 10.1158/2159-8290.CD-NB2022-0061. PMID: 36194623.
[4] Furlanetto J, Marmé F, Loibl S. Sacituzumab govitecan: past, present and future of a new antibody-drug conjugate and future horizon. Future Oncol. 2022 Sep;18(28):3199-3215. doi: 10.2217/fon-2022-0407. Epub 2022 Sep 7. PMID: 36069628.

Featured image: SABCS 2022 San Antonio Breast Cancer Symposium – Tuesday December 6, 2022. Photo courtesy: © 2022 AACR/SABCS/MedMeetingImages/Todd Buchanan. Used with permission.

 

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